In the current work, the effects of design (groove depth and groove width) and operational (temperature and velocity) parameters on aerodynamic performance parameters (coefficient of drag and coefficient of lift) of an isolated passenger car tire have been investigated. The study is conducted by using neural network-based Monte-Carlo analysis on computational fluid dynamics (CFD). The computer experiments are designed to obtain the causal relationship between tire design, operational, and aerodynamic performance parameters. The Reynolds-averaged Navier–Stokes equations-based Realizable K-ε model has been employed to analyze the variations in flow patterns around an isolated tire. The design parameters are varied over wide range and full factorial design, while considering temperature and velocity is completely explored to draw conclusive results. The multi-layer perceptron type neural network with the back-propagation algorithm is trained to map any non-linearity in causal relationships. The sensitivity analysis is performed to find the relationship between control variables and performance indicators. The importance of control variable is determined by both sensitivity and significance analyses and the paired interaction analysis is performed between selected control variables to find the interactive behavior of corresponding variables. The design parameter of groove width with 6.8% and 41% reduction in drag and lift coefficient, respectively, and conventionally overlooked operational parameter of velocity with 4% and 35% impact on drag and lift coefficient, respectively, are found to be the most significant variables. The air trapped between the longitudinal grooves and the road is found to follow the beam theory. The interaction of the groove depth and width is found to be significant with respect to coefficient of lift based on the air beam concept. The interaction of groove width and velocity is found to be significant with respect to both coefficients of lifts and drag.